Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury

John R. Ussher, Wei Wang, Manoj Gandhi, Wendy Keung, Victor Samokhvalov, Tatsujiro Oka, Cory S. Wagg, Jagdip S. Jaswal, Robert Harris, Alexander S. Clanachan, Jason R B Dyck, Gary D. Lopaschuk

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Aims During reperfusion of the ischaemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain depressed. Direct stimulation of glucose oxidation via activation of pyruvate dehydrogenase (PDH), or secondary to an inhibition of malonyl CoA decarboxylase (MCD), improves cardiac functional recovery during reperfusion following ischaemia. However, the effects of such interventions on the evolution of myocardial infarction are unknown. The purpose of this study was to determine whether infarct size is decreased in response to increased glucose oxidation. Methods and Results In vivo, direct stimulation of PDH in mice with the PDH kinase (PDHK) inhibitor, dichloroacetate, significantly decreased infarct size following temporary ligation of the left anterior descending coronary artery. These results were recapitulated in PDHK 4-deficient (PDHK4-/-) mice, which have enhanced myocardial PDH activity. These interventions also protected against ischaemia/reperfusion injury in the working heart, and dichloroacetate failed to protect in PDHK4-/-mice. In addition, there was a dramatic reduction in the infarct size in malonyl CoA decarboxylase-deficient (MCD-/-) mice, in which glucose oxidation rates are enhanced (secondary to an inhibition of fatty acid oxidation) relative to their wild-type littermates (10.8 ± 3.8 vs. 39.5 ± 4.7). This cardioprotective effect in MCD-/-mice was associated with increased PDH activity in the ischaemic area at risk (1.89 ± 0.18 vs. 1.52 ± 0.05 μmol/g wet weight/min). Conclusion These findings demonstrate that stimulating glucose oxidation via targeting either PDH or MCD decreases the infarct size, validating the concept that optimizing myocardial metabolism is a novel therapy for ischaemic heart disease.

Original languageEnglish
Pages (from-to)359-369
Number of pages11
JournalCardiovascular Research
Volume94
Issue number2
DOIs
StatePublished - May 1 2012

Fingerprint

malonyl-CoA decarboxylase
Myocardial Reperfusion Injury
Pyruvic Acid
Oxidoreductases
Myocardial Infarction
Glucose
Reperfusion
Fatty Acids
Reperfusion Injury
Myocardial Ischemia
Ligation
Coronary Vessels
Myocardium
Ischemia
Weights and Measures

Keywords

  • Acute myocardial infarction
  • Glucose oxidation
  • Ischaemia/reperfusion
  • Malonyl CoA decarboxylase
  • Pyruvate dehydrogenase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Ussher, J. R., Wang, W., Gandhi, M., Keung, W., Samokhvalov, V., Oka, T., ... Lopaschuk, G. D. (2012). Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovascular Research, 94(2), 359-369. https://doi.org/10.1093/cvr/cvs129

Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. / Ussher, John R.; Wang, Wei; Gandhi, Manoj; Keung, Wendy; Samokhvalov, Victor; Oka, Tatsujiro; Wagg, Cory S.; Jaswal, Jagdip S.; Harris, Robert; Clanachan, Alexander S.; Dyck, Jason R B; Lopaschuk, Gary D.

In: Cardiovascular Research, Vol. 94, No. 2, 01.05.2012, p. 359-369.

Research output: Contribution to journalArticle

Ussher, JR, Wang, W, Gandhi, M, Keung, W, Samokhvalov, V, Oka, T, Wagg, CS, Jaswal, JS, Harris, R, Clanachan, AS, Dyck, JRB & Lopaschuk, GD 2012, 'Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury', Cardiovascular Research, vol. 94, no. 2, pp. 359-369. https://doi.org/10.1093/cvr/cvs129
Ussher, John R. ; Wang, Wei ; Gandhi, Manoj ; Keung, Wendy ; Samokhvalov, Victor ; Oka, Tatsujiro ; Wagg, Cory S. ; Jaswal, Jagdip S. ; Harris, Robert ; Clanachan, Alexander S. ; Dyck, Jason R B ; Lopaschuk, Gary D. / Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. In: Cardiovascular Research. 2012 ; Vol. 94, No. 2. pp. 359-369.
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